SRP72 and Aplastic Anemia

SRP72 has been implicated in familial cases of aplastic anemia through autosomal‐dominant inheritance, as demonstrated by exome sequencing analyses. In affected families, a heterozygous mutation in SRP72 has been identified and linked to key clinical features of bone marrow failure, including aplastic anemia and myelodysplasia (PMID:22541560). This finding is significant as it adds a novel component to the genetic spectrum underlying these disorders and suggests that defects in protein translocation mechanisms may contribute to disease pathogenesis.

The genetic evidence supporting this association is robust. Two independent families have been reported with heterozygous SRP72 mutations that segregate with disease phenotypes, demonstrating autosomal‑dominant transmission. Detailed case reports illustrate that affected individuals carry mutations that are absent in unaffected members, reinforcing the causative role of SRP72 alterations (PMID:22541560).

Segregation analysis further substantiates this association, with multiple affected relatives in these families showing the presence of pathogenic SRP72 variants. Although precise counts of segregating relatives are not provided, the consistent inheritance pattern across families supports a strong genetic link. This familial clustering is a key piece of evidence for the contribution of SRP72 to the aplastic anemia phenotype.

The variant spectrum includes at least two distinct mutations. A representative pathogenic variant is c.620G>A (p.Arg207His), which alters a critical amino acid residue in SRP72 and is predicted to impair its normal function. This variant, along with others such as a frameshift mutation, highlights the diverse mutational mechanisms by which SRP72 function can be disrupted (PMID:22541560).

Functional studies provide further support for the pathogenicity of SRP72 mutations. In vitro experiments have demonstrated that mutant SRP72 proteins exhibit abnormal intracellular localization and show deficient association with the essential SRP RNA component. These functional defects correlate with the clinical phenotype and help elucidate the mechanism by which SRP72 mutations contribute to disease (PMID:22541560) and are complemented by insights from a mouse model study (PMID:31254415).

Integrating both the genetic and experimental data, the evidence supports a model in which heterozygous mutations in SRP72 lead to defective protein translocation and subsequent bone marrow failure. The concordance between segregation data in affected families and deleterious functional outcomes in experimental models reinforces the clinical validity of this gene‐disease relationship.

Key take‑home message: SRP72 mutations, through a dominant negative or haploinsufficient mechanism, serve as a robust marker for familial aplastic anemia, offering significant clinical utility in diagnostic decision‑making and therapeutic stratification.

References

• American journal of human genetics • 2012 • Exome sequencing identifies autosomal-dominant SRP72 mutations associated with familial aplasia and myelodysplasia PMID:22541560
• European journal of haematology • 2019 • Heterozygous loss of Srp72 in mice is not associated with major hematological phenotypes PMID:31254415

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